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P2‐150: Monoamine oxidase B interacts with gamma‐secretase: Confirmation with a new approach to the proximity ligation assay
Author(s) -
Weiss Sophia Schedin,
Frykman Susanne,
Inoue Mitsuhiro,
Teranishi Yasuhiro,
Winblad Bengt,
Tjernberg Lars
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.2150
Subject(s) - monoamine oxidase b , chemistry , proximity ligation assay , hek 293 cells , microbiology and biotechnology , biophysics , biochemistry , monoamine oxidase , biology , enzyme , gene , receptor
(APP) by b-secretase (mainly BACE1) and g-secretase; a multi-protein complex containing proteolytically active Presenilin-1 (PS1) or Presenilin-2 (PS2). Most mutations in PS1, PS2 or APp, known to cause early-onset AD, predominantly result in an absolute or relative increase in Ab 42 by altered g-secretase cleavage. Since altered g-secretase function is fundamental to the AD process, we hypothesised that proteins or drugs that interact with the secretases may regulate their function and therefore represent potential therapeutic targets. Methods: We have used systems biology technology to search the human proteome for proteins that are known to interact with our seeds BACE1, PS1 or PS2.We then searched these proteins at topological distance 1 (D1) for further interactions at topological distance 2 (D2), focusing on proteins that are expressed in the brain. In addition, we performed a search of D1 and D2 proteins for targets of currently approved drugs.Results:We found 36 (BACE1), 176 (PS1) and 64 (PS2) D1 proteins. Two of the PS1 interactors are known targets for approved drugs (with unknown pharmacological function). In our D2 search, 2 potential g-secretase modulators were highlighted based on their interactions with both PS1 and nicastrin. We also found 5 drug targets (with known pharmacological action) at D2 from PS1 and 3 from BACE1.Conclusions: Our comprehensive search has revealed 15 proteins that interact with PS1 that have not been studied in the field of AD. We are currently verifying these interactions by co-immunoprecipitation and co-localisation in human cell lines. The confirmed interactions will then be investigated for potential modulation of g-secretase activity in vitro. We will also test the effect of the 5 drugs on the interactions of D2 targets to evaluate any potential modulation of Ab production.